The present invention relates to antimicrobial pharmaceutical compositions comprising a combination of a compound of formula (I) with a carbapenem antibiotic or with a .beta.-lactamase inhibitor, to the use of the compositions for producing a medicament for the treatment and prophylaxis of infectious diseases, including MRSA infections, and to pharmaceutical compositions containing the combination.
The extensive use of .beta.-lactam antibiotics during the last decades result in a considerable increase of pathogens resistant to this class of antibiotics. A major threat are infections caused by Methicillin resistant Staphylococcus aureus (MRSA). Various strains of MRSA have been reported to be resistant not only to .beta.-lactams but also to many other antimicrobial agents, including aminoglycosides, erythromycin, chloramphenicol and quinolones.
The compounds of formula (I), also known as vinyl-pyrrolidinone cephalosporin derivatives and their preparation are described in the European Patent Application 841 339, published May 13, 1998. These compounds exhibit a high antimicrobial activity against non-.beta.-lactamase producing strains of MRSA. In .beta.-lactamase-producing strains of MRSA partial hydrolysis of vinyl-pyrrolidinone cephalosporins can occur.
It has now been found that a combination of vinyl-pyrrolidinone cephalosporins of the formula I with .beta.-lactamase inhibitors like, e.g. clavulanic acid, Tazobactam, Sulbactam or (Z)-(2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1-aza-bicyc lo[3.2.0]heptane-2-carboxylic acid (a compound as described in the European Patent Application EP-A-0 640 607) prevents these compounds from being hydrolyzed by staphylococcal .beta.-lactamase thus, resulting in a synergistic effect.
Carbapenems like, e.g. Imipenem or Meropenem are .beta.-lactam antibiotics that have a broad spectrum of antibacterial activity and are in addition good .beta.-lactamase inhibitors. However they do not have good activity against MRSA.
It has now been found that a combination of vinyl-pyrrolidinone cephalosporins of the formula I with carbapenems also leads to a synergistic effect.
Compared to known combinations of two .beta.-lactam antibiotics as described in the European Patent EP-A-384410, Banyu Pharmaceutical Co. Ltd; and compared to a combination of cephalosporins such as e.g. ceftriaxone and meropenem as described in the Japanese Laid Open Patent Publication JP-02-279627 A, Sumitomo, the combinations of the present invention show a higher efficacy against MRSA.
Furthermore, the combination comprises a unique broad spectrum of antibacterial activity that includes Gram-positive pathogens like, e.g. methicillin-sensitive and methicillin-resistant staphylococci, enterococci, penicillin-sensitive and penicillin-resistant pneumococci and Gram negative pathogens like, e.g. E. coli, E. cloacae, K. pneumoniae, P. vulgaris, S. marcescens, C. freundii and P. aeruginosa.